Gut Microbiota, TMAO & Cardiovascular Health 2022

Researchers from Tufts University recently published results from a large community-based cohort in Arteriosclerosis, Thrombosis, and Vascular Biology. They provide details on the associations between both the intake of animal source foods (ASF) and cardiovascular disease risk among older adults, as well as the portion of that risk that appears to be mediated specifically by Trimethylamine N-Oxide (TMAO) and its derivatives. This study provides further evidence of a link between ASF, gut microbiome pathways, and atherosclerotic cardiovascular disease (ASCVD).

This cohort was comprised of nearly 4,000 participants over 65 years of age from the NIH’s long-running Cardiovascular Health Study. During a median follow-up of 12 years, the risk of ASCVD was greater with each quintile of consumption of unprocessed red meat, total meat, and total ASF, with interquintile hazard ratios of 1.15 (1.01–1.30), 1.22 (1.07–1.39), and 1.18 (1.03–1.34), respectively. Thus, for each additional 1.14 serving of total meat, for example, the risk for ASCVD increased 22%, with 6.32 excess events per thousand person-years after multivariate adjustment.

But in addition to the total increase in risk, the proportion mediated by multiple risk factors was determined. For example, per each additional 1.14 servings of total meat, only 0.8% of the increase in risk was mediated by systolic blood pressure and only 0.6% by total cholesterol levels. Fasting glucose was responsible for a much larger portion of this risk (26.1%) as were fasting insulin levels (11.8%). TMAO and its derivatives mediated 7.8% of the risk, a larger portion than C-reactive protein (6.6%). Additionally, TMAO and metabolites mediated 10.6% and 9.2% of the increased risk associated with unprocessed red meat and ASF, respectively. Thus, a greater portion of the increase in risk for ASCVD associated with meat consumption can be linked to the microbiome and glycemic control rather than to lipid and blood pressure abnormalities. 

This is not the first study that points to TMAO as an important predictor of risk. In JAMA Network Open, the results of a prospective cohort (the Cardiovascular Health Study) with over 5,000 participants were released in May, suggesting that TMAO and its metabolites are also correlated with a greater risk of death. Beginning in 1989, the 65+ year-old participants had plasma TMAO levels checked at baseline, and checked again several years later in most participants, who were followed for a mean of 13 years. Comparing the highest quintile to the lowest and adjusting for potential confounders, TMAO levels were associated with a 30% greater risk of death from all causes, with smaller but significant risks associated with choline, butyrobetaine, and carnitine as well.

There is no shortage of disease associations with TMAO; it has been found to be an independent risk factor for mild cognitive impairmenttype 2 diabetes and hyperglycemiametabolic syndromehypertensionheart failure severity and survival, and pretty substantially with stroke risk, with most studies finding a dose-dependent relationship.

Where is this risky metabolite coming from? TMAO is synthesized by the metabolism of trimethylamine (TMA) containing nutrients such as choline and carnitine, which are found in red meat, eggs, fish, milk, and cheese. Specific gut microbiota cleave a carbon-nitrogen bond, and TMA is then oxidized in the liver by flavin monooxygenases (FMOs), primarily FMO3, to form TMAO. TMAO production is therefore a complex intersection between diet, the composition and activity of the gut microbiota, and the efficiency of specific liver enzymes. For example, a polymorphism in the FMO3 gene has been associated both with reduced TMAO levels as well as a lower risk of cardiovascular death among patients with heart failure.

Specific diets may also play a role in modifying TMAO levels, and select nutrients have the potential to blunt TMAO synthesis primarily by modifying the composition of the microbiome. For example, 5 days of a fasting-mimicking diet was shown to reduce the concentration of TMAO 2-fold, while simply increasing the consumption of vegetables (the control group) had no effect in a small clinical trial. Similar reductions were found during 8 weeks of a vegan diet among participants in a small clinical trial that were regular meat eaters, though after discontinuing the vegan diet, TMAO levels rebounded again. Despite its clear benefit for cardiovascular disease, the Mediterranean diet does not appear to substantially alter TMAO levels.

While human clinical trials are lacking, several botanicals/polyphenols have promising effects on TMAO levels in various models, primarily by modulating the microbiota. Although no human trials have been done, berberine is likely to down-regulate TMAO production via modulation of the microbiota, and resveratrol has been shown to decrease TMAO levels both by modulating the gut microbiome and by increasing bile acid synthesis, in part by increasing gut levels of Lactobacillus and Bifidobacterium. Other plant flavonoids have decreased TMAO levels both by modulating FMO3 activity as well as increasing the relative abundances of the Bacteroides and Lactobacillus genus.

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